Breast cancer is a heterogeneous disease as demonstrated at a genomic level with the description of different breast cancer subtypes with independent clinical outcome [Cancer Cell 2007; 11: 259-273, Cell 2011; 144: 646-674, Nature 2000; 406: 747-752, Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 10869-10874]. Among them, triple negative breast cancer (TNBC) refers to breast cancer that lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the Her2/neu (HER2) receptor, and represents 15% of all breast tumors [Clin. Cancer Res. 2004; 10: 5367-5374]. In TNBC, several membrane and intracellular kinases may be concomitantly activated [Cell 2011; 144: 703-718, Oncogene 2013; 33:148-156]. The PI3K/mTOR and the MAPK pathway are commonly phosphorylated in this tumor type [Oncogene 2013; 33:148-156]. Less frequently activated kinases include STAT1, STAT3 or SRC, among others [Oncogene 2013; 33:148-156]. It is associated with a specific tumor relapse pattern and an increased sensitivity to chemotherapy [Clin. Cancer Res. 2007; 13: 4429-4434, Clin. Cancer Res. 2013; 19: 5533-5540]. By using gene expression analyses it has been classified into seven subtypes with different sensitivities to treatment [J. Clin. Invest. 2011; 121: 2750-2767, Clin. Cancer Res. 2013; 19: 5533-5540]. Although the identification of these different subtypes represents a major advance in cancer, unfortunately the implementation of this classification for therapeutic purposes is unclear [J. Clin. Invest. 2011; 121: 2750-2767]. Therefore, available therapeutic options for patients with TNBC are restricted to standard treatment with chemotherapy [Clin. Cancer Res. 2013; 19: 5533-5540, Cancer Treat. Rev. 2013; 39: 68-76] and the prognosis of TNBC patients is poor due to the limited therapeutic options and the lack of specific targeted agents [Lancet Oncol. 2007; 8: 235-244].
Receptor tyrosine kinases (RTKs) and downstream pathways are involved in the regulation of many cellular functions including proliferation and survival [Cell 2011; 144: 703-718, Oncogene 2014; 33: 148-156, Cell 1990; 61: 203-212, Cell 2000; 103: 211-225] and play a central role in the genesis and/or promotion of different breast cancer subtypes tumors including the triple negative subtype. Using human samples the inventors and other research groups evaluated the kinase profile of TNBCs, observing that a number of RTKs are activated; such as the epidermal growth factor receptor (EGFR), the fibroblast growth factor receptor (FGFR) or the platelet-derived growth factor receptor (PDGFR), among others [Oncogene 2014; 33: 148-156]. In addition, several components of the PI3K/mTOR pathway were phosphorylated in a significant proportion of patients [Oncogene 2014; 33: 148-156, Cancer Res. 2013; 73: 6346-6358]. Interestingly, inhibition of the PI3K route produced a proliferative arrest in cellular models and a growth reduction in tumors implanted in xenografted animals or generated using transgenic models [Oncogene 2014; 33: 148-156]. Of note, clinical studies evaluating drugs targeting single receptors have shown disappointing results suggesting that therapeutic strategies should be designed to inhibit a number of key oncogenic nodes [J. Clin. Oncol. 2013; 31: 2586-2592]. In addition, different studies including those using sequencing approaches have shown the relevance of some components of these signaling routes including the PI3K/mTOR pathway [Cell 2011; 144: 703-718, Nature 2012; 486: 395-399]. Based on the global importance of the activation of RTKs and downstream pathways in TNBC, the development of novel multi-kinase inhibitors that could present polypharmacology against key oncogenic nodes is a main goal and tyrosine kinase inhibitors (TKIs) designed to neutralize their function are in clinical development.
Alterations of the DNA repair machinery seem to be of great significance in this cancer subtype, and particularly in basal-like breast tumors [J. Natl. Cancer Inst. 2003; 95: 1482-1485, Nat. Rev. Cancer 2004; 4: 814-819]. This subgroup is enriched with genes associated with proliferation and DNA damage response, when evaluated by gene expression analyses [J. Clin. Invest. 2011; 121: 2750-2767]. It is enriched with somatic and acquired mutations in DNA repair genes, mainly BRCA1 and BRCA2, involved in the homologous recombination (HR) repair mechanism [Nat. Rev. Cancer 2004; 4: 814-819]. The association between RTKs or its downstream pathways with DNA repair mechanisms is unclear. However, activation of some routes like the PI3K/mTOR pathway has been linked with DNA repair and sensitivity to genotoxic stress [Science 2013; 341: 395-9, EMBO Mol. Med. 2009; 1: 315-322]. In addition, treatment with some TKIs alone or in combination induces DNA damage. Indeed, administration of the multi-tyrosine kinase inhibitor dasatinib, with the anti-HER2 antibody trastuzumab, induced DNA damage, and synergized with chemotherapy [J. Natl. Cancer Inst. 2010; 102: 1432-1446]. Since basal-like tumors show an increase in proliferation and an impairment of DNA repair mechanisms, it would be desirable to identify drugs that would induce DNA damage in addition to providing an anti-proliferative effect.
It is the problem of the present invention to provide improved means of preventing and/or treating TNBC which not only induces DNA damage in said tumors, but also provides an anti-proliferative, tumor-specific effect, such that it does not exhibit adverse side effects.